KR100449943B1 - Device for transdermal electrotransport delivery of fentanyl and sufentanil, and preparation methods thereof - Google Patents

Abstract

The present invention relates to the administration of an improved electrotransport drug for analgesic agents, namely fentanyl and cotentanil. The fentanyl / persentanil is provided as an aqueous salt solution (e.g., fentanyl hydrochloride) dispersed in a hydrogel formulation for use in the electrotransport apparatus 10. In accordance with the present invention, the concentration of fentanyl / ceftenartan in the donor reservoir 26 is maintained above a predetermined minimum concentration, whereby the transdermal electrotransport flux rate of the fentanyl / ceftlanthyl is greater than the concentration of fentanyl / It remains irrelevant.

Description

TECHNICAL FIELD The present invention relates to an electrotransport device for transdermal administration of fentanyl and cotentanil,

Transdermal administration in which the drug is administered by diffusion through the epidermis has advantages over conventional administration methods such as subcutaneous injection or oral administration. Transdermal drug administration avoids the hepatic first pass effect seen in oral administration. Transdermal administration can also alleviate patient complaints associated with subcutaneous injection. In addition, transdermal administration can provide any type of transdermal administration device with a more constant concentration of drug within the patient ' s bloodstream for extended periods of time by an extended controlled administration method. The term " transdermal " administration encompasses the administration of the drug through the body surface, such as the skin, mucous membranes or fingernails of an animal.

The skin acts as an initial barrier in transdermal penetration of the material into the body and appears as the main resistance of the body for transdermal administration of a therapeutic agent such as a drug. Up to now, efforts have been focused on enhancing skin permeability or reducing body resistance for the administration of drugs by passive diffusion. Various methods have been tried to increase the flow rate of the transdermal drug, and in particular, a method using a chemical flow rate enhancer has been attempted.

Another approach to increase the rate of transdermal drug use is to use alternative energy sources such as electrical and ultrasonic energy. Percutaneous administration associated with the electrical is also referred to as electrotransport. The term " electrotransfer " as used herein generally relates to administering a drug through a membrane, such as the skin, mucous membrane or nail. The administration is induced or progressed by an electric force. For example, a useful therapeutic agent may be induced into the tissue circulating agent of the human body by administration of the electrotransport through the skin. A widely used electrotransport process, electrophoresis (or iontophoresis), involves the transfer of charge ions electrically induced. Another type of electrotransport, electroosmosis, involves the flow of liquid, which involves the administration of the drug under the influence of an electric field. Another type of electrotransport process, electroporation, involves the formation of a pore that is temporarily present in the biological membrain by an electric field. The drug may be administered via the pore either passively (i.e., without electrical assistance) or actively (i.e., under the influence of an electrical force). However, in any given electrotransport process, one or more of the above processes, including at least " passivity " diffusion, may occur to some extent at the same time. Thus, the term " electrotransport " as used herein refers to the transmission of one or more drugs that are electrically induced or enhanced, as it should be interpreted as widest as possible, and it is understood that the drug may be administered by one particular mechanism, The drug may or may not have charge, or both may be mixed.

The electrotransport device uses two or more electrodes to make electrical contact with any part of the skin, nail, mucous membrane or other body surface. One electrode, commonly referred to as a " donor " electrode, is an electrode that administers a drug into the body. Other electrodes, commonly referred to as " counter " electrodes, act to close the electrical circuit through the body. For example, if the administered drug is positive, i. E. A cation, the anode is the donor electrode and the cathode is the counter electrode to complete the circuit. Alternatively, if the drug is negative, i. E. Anion, then the cathode is the donor electrode and the anode is the counter electrode. Additionally, if both the anionic drug and the cationic drug ions, or the dissolved drug without charge, are administered, both the anode and the cathode may be considered donor electrodes.

In addition, the electrotransport administration system requires one or more sources or reservoirs of the drug to be administered into the body. Examples of such donor reservoirs include pouches or cavities, porous sponges or pads, and hydrophilic polymers or gel matrices. Such a donor reservoir is electrically connected and disposed between the anode or cathode and the body surface to provide a fixed source or recycling source for one or more drugs or agents. The electrotransport device typically also has a power source, such as one or more batteries. Typically, one pole of the power source is electrically connected to the donor electrode, and the opposite pole is electrically connected to the counter electrode. Since the rate of administration of the electrotransport drug appears to be approximately proportional to the intensity of the current applied by the device, many electrotransport devices generally have an electrical controller that controls voltage, current, or voltage and current applied through the electrodes , And the drug administration rate is adjusted. These control circuits use various electrical components to control the voltage, current, or voltage and current amplitude, polarity, timing, waveform, etc. supplied by the power supply. See, for example, U.S. Patent 5,047,007 to McNichols et al.

To date, common drug electroporation transdermal transdermal devices (e.g., Phoresor, sold by Rhode Island Inc. of Salt Lake City, Utah, Dupelion Ion Sole, available from Mfine Corporation of St. Paul, Minn. Webster Sweat Inducer, model 3600, sold by Worscoin Corporation of Rochester, Pa.), Has used a small power supply and a pair of skin contact electrodes. The donor electrode comprises a drug solution and the counter electrode comprises an aqueous solution of a biocompatible electrolytic salt. The power supply has an electrical controller that adjusts the amount of current applied through the electrodes. The " secondary " electrode is connected to the power supply by a long (e.g., 1 to 2 meter) conductor wire or cable. The wiring connection may be disconnected to limit the movement and activity of the patient. The wiring between the electrodes and the controller may also be annoying and inconvenient to the patient. Other examples of miniature power supplies using " auxiliary " electrode assemblies are described in U.S. Patent 4,141,359 (see Figures 3 and 4), Jacobsen et al., And U.S. Patent 5,006,108 (LaPrade et al. 9) and in U.S. Patent 5,254,081 to Maurer et al.

In recent years, it has been proposed to coat small, independent electrotransport dosing devices over the skin for extended periods of time, or sometimes under the clothes. Such small independent electrotransport dosing devices are described, for example, in US Pat. No. 5,224,927 to Tapper, US Pat. No. 5,224,928 to Slbalis et al., And US Pat. No. 5,246,418 to Haynes et al.

It has recently been proposed to use an electrotransport device having a recyclability controller suitable for using a multi-drug containing device. The drug-containing device is simply separated from the controller when the drug is released, and then connects the new drug-containing device to the controller. In this way, relatively expensive hardware (e. G., Batteries, LED's, circuit hardware, etc.) of the device can be contained within the recycle controller, and relatively inexpensive donor and counterholder mattresses can be incorporated into the single use / May be contained within the device, thereby lowering the overall value of the electrotransport drug administration. Examples of electrotransport devices include a recycle controller, which can be detached from the connection with the drug-containing device, as described in U.S. Patent No. 5,320,597 to Sage, Jr et al., And U.S. Patent No. 5,358,483 to Sibalis , U.S. Patent 5,135,479 (Fig. 12), and Devane et al., British Patent Application 2 239 803, both of which are incorporated herein by reference.

In another development of electrotransport devices, water is a liquid solution that is suitable for administration of electrotransport drugs due to its excellent biocompatibility, as compared to other liquid solutions such as alcohols and glycols, Hydrogels are particularly suitable for use as the reservoir matrix. Hydrogels have a high ballast water content and can quickly absorb water. In addition, hydrogels tend to have good biocompatibility with skin and mucosal members.

Of particular interest in transdermal administration is the administration of analgesics to manage from mild to severe pain. In order to avoid the inherent risks of overdose and the inconvenience of inadequate administration, controlling the rate and interval of drug administration is of particular importance when transdermal administration of analgesic agents.

One class of analgesic agents that can be applied to transdermal routes is synthetic opioids, 4-aniline piperidines. Synthetic opiates, such as fentanyl and any derivative such as sufentanil, are particularly suitable for transdermal administration. These synthetic opiates quickly relieve pain and are characterized by high efficacy and short duration of action. They are estimated to have 80 and 800 times more potency than morphine. These agents are bases whose main component is a cationic amine or the like in an acidic medium.

In an in vivo study to determine plasma concentrations, Thysman and Preat (Anesth. Analg. 77 (1993) pp.61-66) reported that the simple diffusion of fentanyl and pterantanil was due to the presence of citrate Compared with the administration of electrotransport in buffer. Simple diffusion does not produce any detectable plasma concentration. The plasma level that can be reached depends on the maximum flow rate of the drug that can cross the skin and the medicinal dynamic properties of the drug, such as the volume and volume of distribution. Electrotransport administration has been reported to have significantly reduced lag times (i.e., the time required to obtain peak plasma levels) when compared to passive transdermal patches (14 h for 1.5 h). The researchers noted that the analgesic electrotransport could provide control of pain faster than classic patches and that the pulsed release of the drug (by controlling the current) could be comparable to the regular administration of a classical patch Results were obtained. Int. J. Pharma., 101 (1994) pp. 105-113 and V. Int. J. Pharm., 96 (1993) pp. 189-196 (Westfantil) and Gourlav et al., Pain, 37 (1989) pp. 529-531 (fentanyl and ceftetanium). For example, passive administration by electrical assisted transdermal administration and diffusion of subtilisin analgesics, such as fentanyl, to induce analgesia is also disclosed in the patent document. See, for example, U.S. Patent Nos. 4,588,580 to Gale et al and U.S. Patent 5,232,438 to Theeuwes et al.

Over the last few years, attention has been paid to the administration system rather than the electrotransplant administration to alleviate postoperative pain. In particular, it should be noted that, within a predetermined range, it is an object of the present invention to provide an apparatus and a system for controlling the amount of analgesic that a patient receives. This type of device results in the patient administering a small amount of analgesic to the patient rather than administering the physician prescribed dose to control the analgesic administration. Self-medication or patient-controlled self-administration is known as patient-controlled analgesia (PCA).

A known PCA device is a generally electro-mechanical pump that requires a multi-capacitive power source, for example, a giant alternating current or multi-capacity, multi-battery pack. Due to its enormity and complexity, PCA devices that can be used in general are generally confined to the patient's bed or any other specially fixed location. The PCA device administers the drug to the patient through a catheter that a qualified medical technician must insert into an IV line or an induced vein, artery or other organ. The technique requires that the skin barrier be stepped over to administer the analgesic (see U.S. Patent 5,232,448 to Zdeb). Therefore, when using everyday PCA devices, the PCA requires a high-tech medical technician, since the PCA device must be operated and managed with the accompanying risk of contamination. Also, the everyday PCA devices themselves are somewhat painful because they are used by their skin (i. E., Intravenous or subcutaneous) penetration methods.

The technique has scarcely generated a technique in a transcutaneous electrotransport device method and a method of controlling pain, which can counter the conventional PCA in terms of the amount of drug administered to achieve a reduction in appropriate pain. In addition, for analgesic electrotransport, such as fentanyl transdermal electrotransport administration, which has performance characteristics comparable to patient controlled electrodynamic pumps for intravenous administration of, for example, analgesics and has long-term stability, There was almost no progressive progress to provide hydrogels. There is a need to provide an analgesic in a suitable device for obtaining the convenience of administering the electrotransport within a small and independent patient control device.

The present invention generally relates to an improved electrotransport drug delivery device. In particular, the invention relates to an improved device for the administration of analgesics, in particular fentanyl and fentanyl-like pharmaceuticals, to electrotransport, a process for their preparation, and a composition for use therein.

The present invention will be described with reference to the accompanying drawings.

1 is a perspective view of an electrotransport drug administration device according to the present invention.

Figure 2 is a graph of the concentration of fentanyl HCl versus normalized transdermal electrotransport flux in aqueous solution.

Embodiments of the Invention

The present invention relates to an improved device for the administration of transdermal electrotransport of fentanyl or cotentanil in water-soluble salt form in the preparation for obtaining systemic analgesic efficacy. The present invention is characterized by maintaining a transdermal electrotransport fentanyl / ceftetanol flow rate independent of the drug concentration in the donor reservoir during the electrotransport drug administration period.

The transdermal electrotransport fentanyl flux rate begins to depend on the concentration of the fentanyl salt in the aqueous solution when the concentration of the tentanyl salt falls below about 11 to 16 mM. The 11 to 16 mM concentration is calculated not by the total volume of the reservoir but by the volume of the liquid solvent used in the donor reservoir. That is, the 11 to 16 mM concentration does not include the volume of the reservoir described by the storage matrix (e.g., hydrogel or other matrix) material. Furthermore, the 11 to 16 mM concentration is based on the number of moles of the fentanyl salt, not the moles of the fentanyl free base contained in the donor storage solution.

For fentanyl HCl, a concentration of 11 to 16 mM is equivalent to about 4 to 6 mg / mL. Other fentanyl salts, such as fentanyl citrate, will have slightly different weight-based concentration ranges based on different molecular weights of the counter-ions of this particular fentanyl salt.

When the tentanyl salt is dropped at about 11 to 16 mM, the flow rate of the fentanyl light-emitting electrotransport begins to be significantly skewed, even though the applied electrotransport current is kept constant. Therefore, to ensure the desired fentanyl flow rate to a certain level of applied electrotransport current, the salt concentration in the solution contained in the donor reservoir should be maintained above about 11 mM, preferably above about 16 mM. This aspect of the present invention ensures a predetermined transdermal electrotransport flux rate by the intensity of any specifically applied electrotransport current by maintaining the concentration of the fentanyl salt in the solution above a minimum level.

In addition to the fentanyl, the water-soluble salt of the persentanil also has a minimum aqueous solution concentration at which the transdermal electrotransport flux rate is dependent on the concentration of the cottantyl salt in the aqueous solution. The minimum concentration of sapfentanil is about 1.7 mM and the minimum concentration of sapfentanyl citrate is equal to about 1 mg / mL.

Unless the fentanyl / serfentanil is combined with the storage matrix material, the particular matrix material selected as the donor storage matrix is largely unaffected by the minimum concentration required to ascertain the flow rate of the predictable transdermal fentanyl / cotentanil Do not. In particular, hydrogel matrices tend not to bind fentanyl or cotentanyl, and the hydrogel is a preferred matrix material class for use in the present invention.

When both fentanyl and cetfentanil are basic, the salts of fentanyl and cetfentanil are generally acid addition salts, for example, citrate salts, hydroxides, and the like. The acid addition salt of fentanyl has a water solubility of about 25 to 30 mg / mL. The acid addition salt of sufentanil has a water solubility of 45 to 50 mg / mL. When these salts are placed in a solution (e.g., aqueous solution), the salts dissolve and form protonated fentanyl or cetentanyl cations and counter anions (e.g., citrate or hydrochloride) anions. For example, the fentanyl / cetfentanil cation is delivered from the anodic electrode of the electrotransport dosing device. An anodic electrode has been proposed for the administration of transdermal electrotransport as a method for maintaining the pH stabilization in the anodic reservoir. See, for example, U.S. Patent 5,135,477 to Untereker et al. And U.S. Patent 4,752,285 to Peter Lens et al. These patents also recognize that one of the disadvantages of the electrotransport dosing apparatus is the use of silver anodic electrodes, that is, applying current through the silver anode oxidizes silver (Ag → Ag ⁺ + e ^- ), Electrotransport forms silver cations comparable to cationic drugs for administration to the skin. Silver ion transfer to the skin causes temporary epidermal discoloration (TED) of the skin. According to the teachings in these patents, the cationic fentanyl and cefentanil are preferably formed as a halogen flame (e.g., hydrochloride salt) so that any electrochemically generated silver ion is reacted with the drug counter ion hayeoseo practically insoluble silver halide ^- to form a ^{(Ag + + X → AgX)} . In addition to these patents, WO 95/27530 to Phipps et al. Refers to the use of additional chloride ion sources in donor reservoirs of transdermal electrotransport dosage units, in the form of high molecular weight chloride resins. When percutaneously administering fentanyl or cefentanil by means of an electrotransport using an anodic electrode, these resins provide a sufficient chloride to provide a great effect for preventing skin discoloration associated with silver ion children.

The present invention provides an electrotransport dosage device for administering fentanyl or ceftlanil through the body surface, e.g., skin, in order to obtain analgesic efficacy. The fentanyl or cortitanyl salt is provided as a water-soluble salt solution in the donor reservoir of the electrotransport dosing device.

The single dose of fentanyl administered by transdermal electrotransport is preferably about 20 μg to about 60 μg for an administration time of up to about 20 minutes in a patient having a body weight of 35 kg or more. More preferably about 35 μg to about 45 μg, and most preferably about 40 μg for the time of administration. The device of the present invention also includes means for administering an additional dose of about 10 to 100, more preferably about 20 to 80, for a period of 24 hours to obtain and maintain analgesic effects.

The single dose of pectantyl administered by transdermal electrotransport is preferably about 2.3 μg to about 7.0 μg for an administration time of up to about 20 minutes in a patient having a body weight of 35 kg or more. More preferably from about 4 μg to about 5.5 μg, and most preferably about 4.7 μg during the time of administration. The device of the present invention also includes means for administering an additional dose of about 10 to 100, more preferably about 20 to 80, for a period of 24 hours to obtain and maintain analgesic effects.

Preferably, the fentanyl / ceftlanil-containing anodic storage formulations for percutaneously administering the above-described dosages of fentanyl / ceftlanil by electrotransport comprise an aqueous solution of a water soluble fentanyl / ceftnantyl salt such as HCl or citrate salts do. More preferably, the aqueous solution is contained in a hydrophilic polymer matrix, such as a hydrogel matrix. In order to obtain an analgesic effect, the fentanyl / cetetranil salt is present in an amount sufficient to administer the doses described above percutaneously by the electrotransport for an administration time of about 20 minutes. The fentanyl / cottitanyl salt comprises about 1 to 10 wt% of the donor storage formulation (including the polymer matrix) on the total hydroxide base, more preferably about 1 to 5 wt% of the donor storage formulation on the total hydroxide base do. Although not described in greater detail in the present invention, the applied electrotransport current density is in the range of about 50 to 150 μA / cm ² , and the applied electrotransport current is in the range of about 150 to 240 μA.

The hydrogel containing ananodic fentanyl / cetternanyl salt can be made by any number of materials, but is preferably composed of a hydrophilic polymer material, preferably one having polarity in its natural state, enhancing the stability of the drug do. Polymers of suitable polarity for the hydrogel matrices have a variety of synthetic and naturally occurring polymeric materials. Preferred hydrogel preparations include suitable hydrophilic polymers, buffer solutions, wetting agents, thickeners, water and water-soluble fentanyl or cottitanic salts (e.g., HCl salts). A preferred hydrophilic polymer matrix is a polyvinyl alcohol that has been cleaned and completely hydrolyzed, such as polyvinyl alcohol (PVOH), for example, Mowiol 66-100, available from Hoechst Aktiengesellschaft, have. A suitable buffer solution is an ion exchange resin which is a copolymer of methacrylic acid and divinylnbenzene in the form of both an acid and a salt. One example of such a buffer solution is a mixture of Polacrilin (a copolymer of methacrylic acid and divinylbenzene of Rom & Haas, Philadelphia) and its potassium salt. The mixture of acid and potassium salts is a polymeric buffer, which forms a polacrilin function, which adjusts the pH of the hydrogel to about pH 6. The use of humectants in hydrogel formulations is useful for inhibiting the loss of moisture from the hydrogel. One example of a suitable wetting agent is guargum. Thickening agents are also easy in hydrogel formulations. For example, a polyvinyl alcohol thickener such as hydroxypropylmethylcellulose (e.g., methocel K100MP available from Dow Chemical of Midland) may be used as a thickener when dispensing a hot polymer solution in a mold or cavity Which helps to modify the rheology of the hot polymer solution. Hydroxypropyl methylcellulose increases the viscosity upon cooling and greatly reduces the propensity of the cooled polymer solution to fill the mold or cavity.

In one preferred embodiment, the hydrogel formulation comprising ananodic fentanyl / cotantanyl salt comprises about 10-15 wt% polyvinyl alcohol, 0.1-0.4 wt% resin buffer solution and about 1-2 wt% fentanyl or cottitanyl salt, preferably Include hydrochloride. The rest are raw materials such as water, humectant, and thickener. The hydrogel formulations of the polyvinyl alcohol (PVOH) system are prepared by mixing all materials, including fentanyl or cetethanil salts, in a single vessel at an elevated temperature of about 90 ° C to 95 ° C for at least about 0.5 hours. The hot mixture is poured into a bubble mold and stored overnight at a cooling temperature of about -35 DEG C to crosslink the PVOH. Strong elastomeric gels are suitably obtained for the fentanyl electrotransport until the temperature rises to ambient temperature.

Hydrogel formulations are used in electrotransport devices such as those described below. A suitable electrotransport device comprises an anodic donor electrode, preferably of silver, and preferably a cathodic counter electrode of silver chloride. The donor electrode is electrically connected to a donor reservoir containing an aqueous solution of the fentanyl / cottitanyl salt. As noted above, the donor reservoir is preferably a hydrogel formulation. The counter reservoir includes a hydrogel formulation comprising a solution (e. G., An aqueous solution) of a biocompatible electrolyte, such as citrate buffered saline. The anodic and caustic hydrogel reservoirs have a skin contact area of about 1 to 5 cm ² , preferably about 2 to 3 cm ^2, respectively. The anodic and caustic hydrogel reservoirs are about 0.05 to 0.25 cm thick, preferably about 0.15 cm thick. The applied electrotransport current is about 150 μA to about 240 μA, depending on the analgesic effect desired. Most preferably, the applied electrotransport current is a substantially constant DC current during the administration period.

Will now be described with reference to Figure 1, which describes an electrotransport device that may be used in accordance with the present invention. 1 is a perspective view of an electrotransport device having a display in the form of a light emitting diode (LED) 14 and an action switch in the form of a pushbutton switch 12. Fig. The apparatus 10 includes an upper housing 16, a circuit board assembly 18, a lower housing 20, an anode electrode 22, a cathode electrode 24, an anode reservoir 26, a cathode reservoir 28, And a conforming adhesive (30). The upper housing 16 has a side wong 15 which aids in holding the device 10 on the patient's skin. The upper housing 16 is preferably composed of an elastomer (e. G., Ethylene vinyl acetate) that can be injection molded. The printed circuit board assembly 18 includes a separate electrical component 40 and a battery 32 and a curled integrated circuit 19. The circuit board assembly 18 is attached to the housing 16 by posts (not shown) that pass through the openings 13a and 13b and to attach the circuit board assembly 18 to the housing 16 , And the ends of the column are heated or melted. The lower housing 20 is connected to the upper housing 16 by a bonding portion 30 and the upper face 34 of the bonding portion 30 is connected to the lower housing 20 and the lower housing 20, (Not shown).

On the underside of the circuit board assembly 18 there is a view of the battery 32, which is preferably a button cell battery, most preferably a lithium cell. Other types of batteries may also be used as the power supply 10.

The circuit output (not shown in Fig. 1) of the news board assembly is electrically connected to the openings 23, 23 'in the depressions 25, 25' formed in the lower housing by electrically conductive adhesive strips 42, So that the electrodes 24 and 22 are electrically connected. The electrodes 22 and 24 are electrically and mechanically connected to the upper sides 44 and 44 'of the reservoirs 26 and 28. The bottom sides 46 ', 46 of the reservoirs 26, 28 are connected to the patient's skin through openings 29', 29 in the adhesive 30. With no pushbutton switch 12 depressed, the electrical circuitry on the circuit board assembly 18 will apply a predetermined DC current to the electrodes / reservoirs 22, 22 for a predetermined length, e.g., about 10 minutes, 26 and 24, 28). Advantageously, the device is configured to be capable of audibly and / or visualizing the initiation of the administration of the drug or pill, the interval therebetween, by the audible sound signal of the lit LED 14 or, for example, " beeper & To the user. An analgesic, such as fentanyl, is administered through the skin, e.g., the arm, of the patient for a predetermined interval of administration (e.g., 10 minutes). In practice, the user feedbacks the action time of the drug administration interval by the signals of both or both of them.

The anodic electrode 22 preferably includes silver, and the cathode electrode 24 preferably includes silver chloride. The two reservoirs 26 and 28 preferably comprise a polymeric hydrogel material as described above. The electrodes 22, 24 and the reservoirs 26, 28 are held by the lower housing 20. For fentanyl and cortitanyl salts, the anodic reservoir 26 is a "donor" reservoir containing the drug and the cathode reservoir 28 comprises a biocompatible electrolyte.

The push button switch 12, the electrical circuit on the circuit board assembly 18 and the battery 32 "seal" between the upper housing 16 and the lower housing 20 with an adhesive. The upper housing 16 is comprised of rubber or other elastomeric material. The lower housing 20 can be easily molded to form the depressions 25 and 25 'and can be easily cut to form the openings 23 and 23', such as plastic or elastomeric sheet materials ). The above assembling apparatus 10 is desirably moisture-resistant (i.e., water-repellent) and most preferably water-repellent. The system can be of a small shape so that it can be easily integrated with the body so that it can move freely around and in the area in which it is worn. The anode / drug reservoir 26 and the cathode / salt reservoir 28 are disposed on the skin-related side of the device 10 and are sufficiently separated to prevent accidental electrical breaks during routine adjustment and use.

The device 10 is attached to the patient's body by a peripheral adhesive portion 30 having an upper side 34 and a body contacting side 36. The bond portion side 36 has adhesive properties such that the device 10 is maintained in place in the body during normal user activity and is conveniently removed after a predetermined attachment period (e.g., 24 hours). The upper adhesive side 34 is affixed to the lower housing 20 and retains the lower housing 20 attached to the upper housing 16 as well as the electrode and drug reservoir in the housing depression 25 and 25 ' .

The push button switch 12 is disposed on the top of the device 10 and is easily operated through the clothes. During a short period of time, for example three seconds, pushing the push-button switch 12 twice activates the device 10 for administration of the drug, thereby minimizing the inadvertent actuation of the device 10. [

Activating the switch signals that the alarm signal has initiated drug administration and the circuit supplies a predetermined level of DC current to the electrode / reservoir for a pre-determined dose interval (eg, 10 minutes). The LED 14 maintains an " ON " state during the dosing interval, indicating that the device 10 is in the drug administration mode. Preferably, the capacity of the battery should be sufficient to continuously supply power to the device 10 with a predetermined intensity of DC current for a total attachment period (e.g., 24 hours).

The present invention will also be illustrated by the following examples, which are merely illustrative of the present invention, and thus the scope of the present invention is not limited thereto.

The present invention provides an electrotransport device for transdermal administration of fentanyl and fentanyl analogs, in particular cotetanil, and a process for its preparation. For example, the device of the present invention is excellent in the efficacy of the electrotransport administration of the analgesic agent fentanyl or sufentanil, and at the same time, in terms of patient stability and patient's pain management. Other advantages in addition to the abovementioned advantages of the present invention are that it provides an apparatus which is capable of administering fentanyl or ceftlanil by electrotransport through the body skin (e.g., natural skin), said device comprising fentanyl / And an anodic donor reservoir at least partially containing an aqueous solution of the salt.

The present invention relates to maintaining the concentration of the fentanyl or cottitanyl salt in the donor storage solution at a level above the level at which the percutaneous flow rate of the fentanyl or cotetanil begins to depend on the concentration of the drug in the solution. For fentanyl, the transdermal electrotransport flux rate remains practically independent of the fentanyl concentration at a fentanyl concentration of about 11 to 16 mM or higher during the fentanyl electroproport administration period. By maintaining the concentration of the fentanyl salt solution at or above about 11 to 16 mM in the donor reservoir, the electrotransport flux rate of the drug is practically maintained independent of the drug concentration in the donor storage solution, and the electrotransport drug administration Lt; / RTI > is practically proportional to the magnitude of the electrotransport current applied by the dosing device. Maintaining a fentanyl salt aqueous solution concentration of greater than about 11 mM and preferably an aqueous solution concentration of the fentanyl salt solution of greater than about 16 mM authenticates a given fentanyl flow rate with a specially adapted transport current.

For serfentanyl, transdermal electrotransport flux rates are maintained independent of ceftanel concentration at or above about 1.7 mM practically during the sustenanti electrotransport administration period. By maintaining the concentration of the ceftanyl salt aqueous solution at or above about 1.7 mM in the donor reservoir, the electrotransport flux rate of the drug remains virtually independent of the drug concentration in the donor reservoir solution, and during the administration of the electrotransport drug, Lt; RTI ID = 0.0 > electro-transport < / RTI > Maintaining the solution concentration of the cetentanate salt solution at about 1.7 mM or more ensures a certain cetentanil flow rate with a specially applied electrotransport current.

Certain applications of the present invention, changes in components and other advantages and complete recognition of the physical accessories will be apparent from the following drawings, detailed description, examples and appended claims.

Example 1

To demonstrate that the transdermal electrotransport fentanyl flow rate is approximately proportional to the magnitude of the applied electrotransport current, the following experiment was performed to determine the required minimum concentration of the fentanyl salt in the donor reservoir of the transdermal electrotransport dose device .

An anodic donor storage gel with a change in loading of fentanyl (HCl) is prepared with the following components:

The combination of Polacrilin and NaOH acts as a buffer to maintain the pH of the gel at about 5.5. Polarcylin (also known as Amberlite IRP-64) is sold by Rohm and Haas of Philippe, PA. The material is mixed in a beaker at an elevated temperature of 90 ° C to 95 ° C, poured into a bubble mold and then stored overnight at -35 ° C to crosslink with PVOH. The gel has a skin contact area of 2 cm ² and a thickness of 1.6 mm. The gel had a concentration of fentanyl HCl of 21 mg / mL in water. Silver foil-atomic electrodes were laminated on one surface of the gel.

The transdermal transport fentanyl flow rates from these gels were determined by in vivo flow studies using two component diffusion cells and invasive skin. The gel was placed on the transdermal stratum corneum of a dissected dissected body obtained from a skin sample. The other side of the sheath is filled with Dulbecco's phosphate buffer (pH 7.4), which is exposed to the receptor portion, having a volume of 4 cm < ² > and having a strength of 1/10. A counter electrode composed of a polyisobutylene membrane loaded with silver chloride powder is placed in the receiver section.

The donor and counter electrodes are electrically connected to a galvanostat configured to apply a constant DC current of 200 μA (ie, 100 μA / cm ² ). The current is applied continuously for 16 hours and the receptor portion is sampled hourly for 16 hours.

Six identical flow rate experiments were performed with different skin samples and transdermal flow rates were averaged 6 times. The transdermal fentanyl flow rate is increased during the first 8 hours of application of the current, and then remains almost constant (i.e., the steady state flow rate reaches after 8 hours). The fentanyl concentration was calculated from the original fentanyl content in the donor gel, subtracting the amount of fentanyl administered to the receptor solution through the skin and dividing by the weight of water in the gel.

The normalized transdermal fentanyl flow rate, calculated as a percentage of the steady state transdermal flow rate, was plotted against the fentanyl concentration in the gel, as shown in Fig. As can be seen in Figure 2, the normalized flow rate is maintained at 100% or near 100% at a fentanyl HCl concentration of at least about 6 mg / mL. The normalized flow rate begins to fall when the fentanyl HCl is below 6 mg / mL, especially below about 4 mg / mL. When this result is below about 6 mg / mL, the greater part of the applied electrotransport current is carried by ions other than the fentanyl ion, and the fentanyl flow rate is more dependent on the fentanyl HCl concentration. Therefore, it is desirable to maintain the concentration of fentanyl HCl in the donor reservoir at about 6 mg / mL or more, in order to identify the desired fentanyl flow rate to a certain level of applied electrotransport current.

Example 2

The two fentanyl hydrochloride-containing Anodic Donor Store PVOH-based gels have the following constituents.

In both formulations, the purified water and PVOH are mixed at a temperature between 92 [deg.] C and 98 [deg.] C, fentanyl hydrochloride is added, and then mixed again. The liquid gel is pumped into a bubble mold having a cavity in the form of a disk. The mold is placed in a refrigerator at -35 [deg.] C to crosslink with PVOH. The gel may be used as an anodic donor reservoir suitable for transdermal electrotransport fentanyl administration.

To summarize, the present invention provides an improved apparatus for transdermal electrotransport of the fentanyl and ceftlanil host salts. The electrotransport device preferably has a silver anodic donor electrode and a hydrogel based donor reservoir. The electrotransport device is preferably a patient control device. Hydrogel formulations contain sufficient drug concentration to maintain a transdermal electrotransport drug flow rate for a given current strength and to provide an acceptable level for analgesia.

Claims (14)

An electrorotransport apparatus (10) for administering an analgesic agent selected from the group consisting of a fentanyl salt and a cottentanil salt through a body surface by means of an electrotransport, comprising: a donor reservoir containing at least a part of an aqueous solution of a fentanyl salt or a cottitanyl salt (26), characterized in that, in the electrotransport apparatus (10) The reservoir 26 is sufficient to maintain the concentration of the tentanyl salt in the solution above about 1.7 mM, at a level above the level at which the electrotransport flux rate of the drug is dependent on the concentration of the drug salt in the solution, during practically the analgesic electrotransport administration interval Wherein the electrotransport device comprises a positive serotentanil salt. The electrotransport device according to claim 1, wherein the drug is a fentanyl salt, and the reservoir (26) comprises an amount of the fentanyl salt sufficient to maintain the concentration of the fentanyl salt in the solution at about 11 mM or higher. The method of claim 1, wherein the donor reservoir (26) comprises a hydrogel comprising an aqueous solution of a fentanyl salt, wherein the solution has a concentration of fentanyl in the hydrogel of at least about 5 mg / Port device. The method of claim 1, wherein the donor reservoir (26) comprises a hydrogel comprising an aqueous solution of a shelfitanium salt, wherein the solution has a shelfentanil concentration in the hydrogel of at least about 1 mg / Device. The electrotransport device according to claim 1, characterized in that the device (10) is applicable to natural skin. 2. The electrotransport device according to claim 1, wherein the device (10) is applicable to human natural skin. 2. The electrotransport device according to claim 1, wherein the electrotransport flux rate of the analgesic agent is substantially proportional to the magnitude of the electrotransport current applied by the electrotransport drug dosing device (10). A method for preparing an electrotransport administration device (10) for administering an analgesic agent selected from the group consisting of a fentanyl salt and a cottental salt through an electrotransport through a body surface, the method comprising the step of adding an aqueous solution of a fentanyl salt or a cotentanyl salt In a donor reservoir (26), the method comprising the steps of: Substantially, during an analgesic electrotransport administration period, at a level above the level at which the electrotransport flux rate of the drug depends on the concentration of the drug salt in the solution, the concentration of the fentanyl salt in the solution is maintained at about 11 mM or higher and the concentration of the sustantan salt in the solution Wherein the fentanyl or cottitanyl salt is sufficiently contained in the reservoir to maintain the concentration of the fentanyl compound at about 1.7 mM or more. 9. The method of claim 8, wherein the drug is a fentanyl salt, wherein the concentration of the fentanyl salt in the solution is maintained at about 16 mM or higher. 9. The method of claim 8, wherein the donor reservoir (26) comprises a hydrogel comprising an aqueous solution of a fentanyl salt, wherein the solution has a fentanyl concentration of at least about 5 mg / ml in the hydrogel. 9. The method of claim 8, wherein the donor reservoir (26) comprises a hydrogel comprising an aqueous solution of a surfactant, wherein the solution has a sapphantane concentration in the hydrogel of at least about 1 mg / . The method according to claim 8, wherein the body surface is natural skin. 9. The method according to claim 8, wherein the body surface is human natural skin. The method of claim 8, wherein the electrotransport flux rate of the analgesic agent is substantially proportional to the magnitude of the electrotransport current applied by the dosing device (10) during administration of the electrotransport drug.

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